Stroke and Systemic Lupus

Erythematosus: A Review

Authors: Marco Cavallaro, Ugo Barbaro, Antonio Caragliano, Marcello Longo,

Giuseppe Cicero, Francesca Granata, *Sergio Racchiusa
Department of Biomedical Sciences and Morphological and Functional Imaging,
University of Messina, Policlinico “G. Martino”, Messina, Italy
*Correspondence to sergioracchiusa@gmail.com

Disclosure: The authors have declared no conflicts of interest.

Received: 15.03.18

Accepted: 04.06.18

Keywords: Endothelium, inflammation, intracerebral haemorrhage (IH), stroke, subarachnoid

haemorrhage (SAH), systemic lupus erythematosus (SLE).

Citation: EMJ Rheumatol. 2018;5[1]:100-107.

Abstract
Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease that involves
collagen tissue throughout the body. Several previous studies have shown that the risk of ischaemic
and haemorrhagic stroke is significantly higher in SLE when compared to the general population,
particularly in young individuals, representing one of the principal causes of death in these
patients. Though the precise pathophysiology behind this increased risk is still poorly understood,
several mechanisms are suggested to play a role. The high burden of cerebral small vessel disease
features noted on brain neuroimaging studies, as well as the accelerated process of atherosclerosis
identified in these patients, are likely to be responsible for at least some of the ischaemic strokes
occurring in the SLE population. Repeated episodes of arterial and venous thrombosis secondary
to antiphospholipid syndrome are likewise important. Less is known regarding the exact
pathophysiological relationship between SLE and the high incidence of haemorrhagic stroke,
though thrombocytopenia and a greater susceptibility to form typical and atypical brain aneurysms,
which may then rupture, are thought to be the main mechanisms responsible for the occurrence of
intracerebral and subarachnoid haemorrhage, respectively. Both inflammatory and noninflammatory
events, all involving the immune system, are responsible for several pathological changes affecting
cerebral vessels of every calibre in SLE, as confirmed by histopathology. In this context, endothelial
activation and dysfunction play a critical role. This review will briefly analyse the most important
factors responsible for the higher ischaemic and haemorrhagic stroke risk in the SLE population,
with a particular focus on brain vascular changes.

INTRODUCTION Numerous studies have shown that individuals

Systemic lupus erythematosus (SLE) is a chronic
autoimmune disorder that causes inflammation
in connective tissues throughout the body.
Prevalence ranges from a few to 241 cases per
100,000 people, with women and people of
black ethnicity being more frequently affected.1
with SLE have a higher risk of cerebrovascular
events than the general population.2,3 Stroke
and cerebrovascular events in general are
among the main specific causes of death in SLE
patients, representing 10–15% of all deaths in
this population.4

100 RHEUMATOLOGY • July 2018 EMJ EUROPEAN MEDICAL JOURNAL

 Box 1: Principal factors implicated in the higher stroke incidence in systemic lupus erythematosus patients.

Ischaemic stroke
>> Higher burden of cerebral small vessel disease.
>> Accelerated atherosclerosis.
>> Antiphospholipid syndrome and arterial and venous thrombosis.
>> Cerebral vasculitis.
>> Vessel dissection.
>> Other minor factors (e.g., cardiogenic thromboemboli in Libman–Sacks disease; infections).
Haemorrhagic stroke
>> Intracerebral haemorrhage
>> Thrombocytopenia.
>> Anticoagulants.
>> Secondary hypertension.
>> Cerebral vasculitis.
>> Other factors (haemorrhagic transformation of ischaemic infarction; other disorders of blood coagulation).
>> Subarachnoid haemorrhage
>> Typical aneurysm rupture (saccular or ‘belly’ aneurysm).
>> Atypical aneurysm rupture (distal fusiform aneurysms, multiple aneurysms with atypical locations).
>> ‘Angiogram-negative’ subarachnoid haemorrhage.

It has been demonstrated that in patients with
SLE, the risk of any kind of stroke, ischaemic
or haemorrhagic, is higher when compared to
the general population, particularly in patients
<50 years old.2,5,6 Specifically, studies have
reported a 2-fold increased risk for ischaemic
stroke and 2–3-times greater risk for intracerebral
haemorrhage (IH) in SLE patients in comparison
with the general population.2,5 Moreover, apart
from overt neurological syndromes, silent
vascular damage, evaluated with MRI, is
augmented in SLE.5 Subarachnoid haemorrhage
(SAH) also seems more frequent in SLE
patients compared to the general population,
with a reported incidence rate of 49.4 versus
10.2 per 100,000 person-years.7 Although the
exact mechanisms responsible for the increased
stroke risk in SLE are not yet fully understood,
numerous hypotheses have been formulated.
The aim of this review is to analyse the different
factors contributing to the higher risk of stroke
in the SLE population, with a focus on cerebral
vascular changes (Box 1).
numerous central nervous system pathological
manifestations.8 Both inflammatory and
noninflammatory events affect cerebral vessels
of every calibre. As further described below,
all cerebral vessels, from large arteries to small
vessels to veins, can potentially be involved
in SLE.
Such a diffused vascular participation has been
confirmed by numerous pathological studies
reporting several changes affecting brain
vessels, ranging from thrombosis, perivascular
infiltration of inflammatory cells, and destructive
and proliferative changes, comprising fibrinoid
degeneration and endothelial cell proliferation.9,10
All of these mechanisms involve the immune
system with different events: immune
complex/complement injury, vasculopathy
due to antiphospholipid (aPL) antibodies
or dysfunctional platelets, plasma factors,
endothelial cell adhesion molecules, and overt
clotting due to aPL antibodies resulting in
thrombosis or cardiac emboli to the brain.11

It would appear that the key factor in

CEREBRAL VASCULAR CHANGES IN
the pathogenesis of all of these events is
SYSTEMIC LUPUS ERYTHEMATOSUS endothelial cell damage and/or activation.8,12,13
AND THE ROLE OF ENDOTHELIUM It is known that one of the main mechanisms
involved is the direct binding of autoantibodies
It is widely known that vascular involvement to certain molecules expressed on the surface of
in SLE is a key factor for the development of endothelial cells, such as beta 2 glycoprotein I,

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 which is considered to be among the most
important.12 This process, together with immune
complex depositions, increases complement-
dependent cytotoxicity and endothelial
permeability and leads endothelial cells to
express adhesion molecules, which attract
circulating lymphocytes and monocytes.
Atehortúa et al. have also hypothesised a
14
possible interaction of different monocyte
subpopulations with endothelial cells, favouring
alterations in the macro and microvascular
context of SLE. The combination of these
processes leads to prothrombotic activity
induction, leukocyte subendothelial infiltration,
and detachment of endothelial cells; for
example, an increased number of circulating
endothelial cells have been found in the blood
of patients with SLE.15 A peculiar susceptibility
of the brain endothelium to these inflammatory
mediators in comparison with endothelial
cells from other anatomical regions has also
been hypothesised.12
ISCHAEMIC STROKE
Cerebral Small Vessel Disease
One of the hypotheses for the higher stroke
incidence in SLE patients is related to the
association between SLE and cerebral small
vessel disease (CSVD).
The term CSVD refers to various pathological
processes affecting the perforating cerebral
arterioles, capillaries, and venules of the brain,
with subsequent parenchymal damage, mainly
in the white matter and in the subcortical grey
matter.16 CSVD is very common, accounts for
approximately 20% of all strokes, and increases
the risk of future strokes by >50%;17 symptoms
include cognitive and balance impairment and
dementia. Neuroimaging, particularly MRI,
is essential for the diagnosis of CSVD, and
some scores based on MRI features, such as
lacunes, white matter hyperintensities, cerebral
microbleeds, and enlarged perivascular spaces,
have been developed to calculate a total CSVD
burden, thus providing a standardised language
and a baseline stratification of patients with
CSVD.18 Using MRI features, Wiseman et al.19
showed that patients with SLE have a high
burden of CSVD; MRI-dependent CSVD score
was higher in SLE patients when compared to
102 RHEUMATOLOGY • July 2018 EMJ
both healthy control patients and patients with
minor stroke, despite the latter presenting more
traditional cardiovascular risk factors.
Although the correlation between SLE
and CSVD is not yet fully understood, it is
hypothesised that inflammation, as it is the
underlying factor in SLE, might well play an
important role in the pathogenesis of CSVD.
Pathological studies have showed inflammatory
infiltrates in the perforating arteriolar walls,20
and some authors have reported an association
between the levels of C-reactive protein (CRP)
and CSVD-related lesions.21 Moreover, enlarged
perivascular spaces, the MRI feature mainly
responsible for the higher CSVD score in SLE
patients,19 have been shown to be associated with
increased plasma markers of inflammation,22 as
well as with other inflammatory brain disorders
such as multiple sclerosis.23 Therefore, it is likely
that some endothelial damage risk factors
occurring in SLE, such as complement activation
and immune complex deposition, could stimulate
cerebrovascular inflammation, causing a high
burden of CSVD, and are responsible for at least
some of the ischaemic strokes in SLE patients.19
Accelerated Atherosclerosis
Numerous studies have identified an accelerated,
premature process of atherosclerosis as one
of the leading causes of the elevated risk of
ischaemic stroke and cardiovascular events in
patients with SLE.24-28 Various hypotheses have
been formulated to explain this phenomenon.
Firstly, an increased prevalence of several
traditional risk factors for atherosclerosis have
been shown in the SLE population. Hypertension
in particular has been found to be the most
important traditional factor associated with
SLE.27 Diabetes also seems to be more common
in SLE patients than the general population.6,26
Furthermore, these patients are more likely to
have a more sedentary lifestyle, higher very low-
density lipoprotein-cholesterol and triglycerides,
and lower high-density lipoprotein.24,26
However, traditional risk factors alone fail to
explain the excess risk of atherosclerosis in
SLE patients,29 especially when the trend for
higher stroke risk in people <50 years old is
considered. A further confirmation also comes
from some studies that found SLE to be
associated with a high burden of early
EUROPEAN MEDICAL JOURNAL
 atherosclerosis even after adjustment for classic
risk factors was made.28,30 Therefore, other
SLE-related factors must be considered to
explain the high atherosclerotic burden in these
patients. Once again, systemic inflammation
seems to play a pivotal role in the atherogenic
process. It is known that inflammation is
involved in all stages of atherogenesis, from
the formation and evolution of atheroma to
the thrombotic complications of this disease.31
CRP has been demonstrated to be an active
mediator in the pathogenesis of atherosclerosis,31
and elevated levels of CRP have been
found during the course of SLE, even
in patients with inactive disease,27 thus
representing another factor involved in the
accelerated atherosclerosis in SLE. SLE-related
inflammation also contributes to several
dyslipidaemic alterations associated with the
development of atherosclerotic disease, such
as hypercholesterolaemia, hypertriglyceridaemia,
and the reduction in activity of lipoprotein
lipase and other antioxidant enzymes.26
Autoimmune phenomena also play an
important role in the atherogenic process.
SLE-circulating immune complexes have
been shown to stimulate the accumulation of
cholesterol in cultured smooth muscle cells.32
SLE autoantibodies, such as double strand-DNA
autoantibodies and, when present, aPL
antibodies, stimulate endothelial activation,
which is considered one of the main and earliest
steps in the atherogenic process. Enhanced
endothelial activation is also demonstrated by
the increased serum levels of some markers, such
as vascular cell adhesion molecule-1 (VCAM-1),
thrombomodulin, and von Willebrand factor,
which have been shown to be augmented in
SLE patients, even with inactive disease.27
Another important element in the development
of atherosclerosis in the SLE population is an
altered vascular remodelling, as proven by the
elevated levels of some metalloproteinases,
like MMP-3, found in the serum of these
patients, and this increased activity has
been demonstrated during many steps of
atherosclerosis.27,33 Several studies have shown
that disease duration and damage index are
also directly related to atherosclerosis.25,28,29
Conversely, the role of treatment, especially
steroids, has not yet been fully established.
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Most authors have reported a direct correlation
between elevated exposure to corticosteroids
and the process of atherosclerosis.26,34 Roman
et al.,28 on the other hand, found that SLE
patients with carotid plaque presented lower
average dose of prednisone than SLE patients
without plaque. Antimalarials, in contrast, have
generally been considered to have a beneficial
anti-inflammatory and antiplatelet effect
and have been associated with lower total
cholesterol and triglyceride levels.26,35 Other
nontraditional factors, such as chronic renal
impairment and homocysteine levels, have also
been related to the accelerated atherogenesis
occurring in SLE.24,27
Antiphospholipid Syndrome
and Thrombosis
It has been noted that 25–40% of SLE patients
have secondary aPL syndrome (APS),
characterised by the presence of aPL antibodies
with clinical features of repeated episodes
of arterial or venous thrombosis, recurrent
spontaneous abortions, or thrombocytopenia.36
APS is a disorder characterised by thrombosis,
which can be either venous, arterial, or
both, and pregnancy loss in conjunction
with the presence of lupus anticoagulant,
or IgG or IgM anticardiolipin, or IgG or IgM
anti-β2-glycoprotein I.37 The syndrome can be
primary, when it occurs in the absence of any
other related disease, or secondary, when it is
associated with other autoimmune diseases,
especially SLE (APS/SLE).36
In 2014, Kaichi et al.38 retrospectively examined
256 SLE patients (45 with APS, 211 without
APS) who had undergone MRI studies. They
found a higher incidence of cerebral lesions
in patients with APS/SLE. Large territorial
infarctions, lacunar infarctions in the deep
white matter, localised cortical infarctions in the
middle cerebral artery (MCA) territory, bilateral
border zone infarctions, anterior basal ganglia,
and stenotic arterial lesions were found to be
more common in SLE patients with APS than
in those without.38 The main factor responsible
for vascular damage in APS/SLE is thought to
be arterial and/or venous thrombosis. Arterial
damage could be divided into large-artery
occlusions (most commonly MCA) or into
multifocal arterial stenoses. Focal regions of
arterial narrowing have been noted within
103
 branches of the anterior, middle, and posterior
cerebral arteries.39
Venous occlusive disease has also been
described in the intracranial circulation;40
occlusion of dural venous sinuses and deep
cerebral veins was reported with a prevalence
of 29% in patients with APS.41
aPL antibodies are a heterogeneous family of
antibodies that react against several anionic
phospholipid-binding plasma proteins.12
The presence of this family of autoantibodies
in the serum, operating through cofactors
(β2-glycoprotein I or prothrombin), can
generate a thrombotic diathesis. Although the
mechanism for this hypercoagulable state is
not yet fully understood, it appears to involve
interactions between the antibodies to anionic
phospholipid-protein complex and antigen
targets on platelets, endothelial cells, or
components of the coagulation cascade.42
Therefore, APS is likely to represent a key factor
in the origin of ischaemic and venous stroke
in SLE patients, as also reported by Valdés-
Ferrer et al.,43 who described a higher prevalence
of strokes and leukoaraiosis in patients with
APS/SLE than in those patients with only SLE.
Vasculitis
A true cerebral vasculitis in SLE is rare,
with a reported incidence in pathological
studies of <10%.44 Clinical manifestations are
highly variable, due to the potential of the
inflammatory process to affect vessels of
different sizes, and can range from mild
cognitive impairment to severe neurological
manifestations, including stroke, both ischaemic
and haemorrhagic.12 The involvement of large
vessels is extremely rare and has been associated
with the most serious neurological manifestations
and extremely high mortality rates.45,46
The main pathophysiological processes implied
are the in situ formation or the deposition of
immune complexes within the vessel wall and
the action of antibodies against endothelial
cells.13 Specifically, it has been shown that
autoantibody binding to brain endothelial cell
antigens can induce an endothelial activation
eventually responsible for the vasculitic process.12
104 RHEUMATOLOGY • July 2018 EMJ
Other forms of SLE-related vasculitis can be
drug-induced or infection-related, in the latter
case either through direct damage of the
vascular wall by micro-organisms or through
antigen-induced autoimmune processes.13
Dissection
Arterial dissection is considered a very rare
cause of ischaemic stroke; indeed, it has been
reported that internal carotid artery dissection is
responsible for <2% of all ischaemic strokes.47,48
Similar to other connective tissue diseases,
SLE has a higher risk of vascular dissection.
The pathophysiological correlation between
SLE and arterial dissection is not clearly
known. Many factors may play a role and can
co-operate,49 determining a self-sustaining loop.
Numerous factors are involved in the activation
of autoinflammatory degeneration of vessel
walls, such as endothelial and extracellular
matrix damage, immune complex formation,
and deposition.5,50
The chronic use of steroids induces arterial
weakening and, along with hypertension,
dyslipidaemia, and increased arterial stiffness,
can lead to arterial wall dissection.
Despite the infrequent occurrence, when
considering the possible aetiology of a SLE
patient presenting with ischaemic stroke, the
possibility of arterial dissection should be
considered. Conversely, in a young patient
presenting with stroke due to arterial dissection
of unknown origin, it is mandatory to investigate
a contingent coexistence of a rheumatic
disease, such as SLE.51
HAEMORRHAGIC STROKE
Intracerebral Haemorrhage
IH in the SLE population is rarely reported in
the literature.2,6,52,53 It has been shown that,
compared to the general population, SLE
patients present a 2–3-fold higher risk of IH,
especially at younger ages.2,5,52
Several factors, most of which are also
associated with ischaemic stroke, are implicated
in the pathogenesis of IH in SLE. One of
the most important is considered to be
thrombocytopenia, diagnosed in >50% of
affected patients, which can be secondary to
EUROPEAN MEDICAL JOURNAL
 different mechanisms, such as the administration
of immunosuppressive agents, the presence of
aPL antibodies, thrombotic microangiopathy,
and bone marrow depression.54,55
Another important factor contributing to
the high risk of IH in the SLE population is
represented by the frequent use of
anticoagulants to prevent thromboembolism
events. This could also represent one of the
reasons for the observation some authors
have made that the longer the time from SLE
diagnosis, the higher the relative risk of IH.6
The high prevalence of hypertension in the
SLE population is another factor that is highly
associated with a possible diagnosis of IH
in these patients.27 Furthermore, vessel wall
weakness, due to endothelial dysfunction or
to a concurrent true vasculitic process, may
be responsible for a major propensity of the
vessel to rupture, thus causing IH.2,52 Eventually,
the possibility of haemorrhagic transformation
of an ischaemic infarction, especially after
thrombolytic therapy, must also be considered.56
An interesting element confirming the more
complex pathogenesis of IH in SLE patients in
comparison with IH in the general population
is the different anatomical localisation of the
haemorrhages in the brain, which are often
located in the cerebral lobes in the former group
compared to the basal ganglia and internal
capsule in the latter cases.52,57
Subarachnoid Haemorrhage
Several studies have showed a relatively frequent
occurrence of SAH in SLE patients, with some
authors reporting an up to 4-fold higher risk
ratio and incidence rate compared to the
general population.2,7
The causes of this increased incidence of SAH
in SLE patients are not yet fully understood.
Similar to the general population, rupture
of intracranial aneurysms appears to be the
most frequent cause of SAH in SLE patients.7
However, most of these aneurysms often
present peculiar features; apart from the
classic saccular (or ‘belly’) aneurysms, as in the
general population, uncommon lesions, like
distal fusiform aneurysms and multiple little
aneurysms with atypical locations, are often
described when SAH occurs in SLE patients.58
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Furthermore, in some cases, SAH is not related
to an obvious pathology, with no aneurysms
or other pathological findings detected in
the angiographic exams performed after
SAH has occurred (the so called ‘angiogram-
negative SAH’).58,59
Several pathophysiological hypotheses
have been formulated to explain the higher
incidence and the peculiar features of SAH in
the SLE population. Once again, the increased
prevalence of several traditional risk factors
for SAH, especially hypertension and
atherosclerosis, as well as endothelial damage,
fibrinoid necrosis, and the activity index,
represent key pathogenic factors for the
onset of SAH, particularly for the greater
likelihood of formation and rupture of classic
saccular aneurysms.58,60
Cerebral vasculitis plays an important role too,
especially in the genesis of atypical aneurysms;
arterial inflammation causes lumen vessel
narrowing and cerebral flow reduction, leading
to ischaemia and haemodynamic stress, which
are cofactors for aneurysmal genesis.7,61
Very little is known regarding the pathogenesis
of angiogram-negative SAH. Treatment-related
complications, especially for corticosteroid
therapy, are likely to be involved in many of these
cases.58,60 In fact, the use of a high daily dose of
steroids has been shown to be an independent
risk factor for an increased incidence of SAH.7,58
CONCLUSION
The risk of any stroke, whether ischaemic or
haemorrhagic, is higher in SLE than the general
population, especially in young individuals.
Several traditional, potentially manageable risk
factors, classically implicated in the genesis of
stroke in the general population, play a critical
role in the SLE population; for some of these
risk factors, an increased prevalence has been
noted in SLE patients compared to the general
population. More attention and control of these
factors (such as hypertension, diabetes, and
anticoagulant dosage) are mandatory. However,
classical risk factors alone fail to explain the
higher incidence of stroke in SLE patients
compared to the general population, especially
when some elements are considered: the high
incidence of stroke in people <50 years old,
105
 the higher CSVD score compared to patients
with a previously occurring minor stroke,
the high burden of atherosclerosis even after
adjustment for traditional risk factors,
the occurrence of atypical or rare events
(e.g., dissection and atypical aneurysms).
Although the precise pathophysiology
responsible is not completely understood,
several mechanisms have been hypothesised;
in this context, inflammation and endothelial
cell activation and damage play a crucial role.
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